Neurotrophins in allergic airway dysfunction: what the mouse model is teaching us.
ABSTRACT Neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are potent mediators of neuronal plasticity in the adult. There is increasing evidence that they regulate a variety of immune functions as well. Thus, neurotrophins are candidate molecules for neuroimmune interactions in allergic bronchial asthma, where elevated neurotrophin levels have been reported. In a mouse model of allergic airway inflammation we have identified macrophages and lymphocytes as additional cellular sources of NGF and BDNF in the inflamed lung. There was an unusual time course of BDNF in bronchoalveolar lavage fluid. BDNF levels peaked 1 week after the last allergen challenge, and did not correlate with the time course of the inflammatory response. In a series of experiments using blocking anti-NGF and anti-BDNF antibodies, we have shown that NGF specifically enhances inflammation and the allergic early-phase response. In contrast, BDNF influenced chronic airway obstruction and local neuronal hyperreactivity without affecting inflammation. Using transgenic mice overexpressing NGF in the airway epithelium, we have confirmed the data obtained from anti-NGF experiments. Allergen-challenged NGF overexpressors displayed a markedly augmented airway inflammation, early-phase response, and sensory irritation compared to wild-type mice. Studies with p75-NTR (-/-) knockout mice showed that these NGF effects are at least in part mediated by the low-affinity neurotrophin receptor. Thus, our experiments suggest that NGF and BDNF have a profound, but differential impact on allergic airway dysfunction.
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ABSTRACT: Brain-derived neurotrophic factor (BDNF) has potent effects on neuronal survival and plasticity during development and after injury. In the nervous system, neurons are considered the major cellular source of BDNF. We demonstrate here that in addition, activated human T cells, B cells, and monocytes secrete bioactive BDNF in vitro. Notably, in T helper (Th)1- and Th2-type CD4(+) T cell lines specific for myelin autoantigens such as myelin basic protein or myelin oligodendrocyte glycoprotein, BDNF production is increased upon antigen stimulation. The BDNF secreted by immune cells is bioactive, as it supports neuronal survival in vitro. Using anti-BDNF monoclonal antibody and polyclonal antiserum, BDNF immunoreactivity is demonstrable in inflammatory infiltrates in the brain of patients with acute disseminated encephalitis and multiple sclerosis. The results raise the possibility that in the nervous system, inflammatory infiltrates have a neuroprotective effect, which may limit the success of nonselective immunotherapies.Journal of Experimental Medicine 04/1999; 189(5):865-70. · 13.21 Impact Factor
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ABSTRACT: Because asthmatic patients show increased nerve growth factor (NGF) serum levels, we examined the effect of NGF on airway function. Intravenously administered NGF potentiates the histamine- induced bronchoconstriction with a maximum of over 200% in anesthetized spontaneously breathing guinea pigs. Doses of 8 ng and 80 ng NGF/kg body weight induce a significant hyperresponsiveness to histamine. NGF itself does not affect airway reactivity. Airway hyperresponsiveness is observed 30 min and 3 h after NGF administration, and has disappeared after 24 h. The neurokinin-1 receptor antagonist SR 140333 completely blocks the NGF-induced hyperresponsiveness, pointing to a role for tachykinins. This is the first report showing a direct relation between peripherally administered NGF and airway hyperresponsiveness. Taking into consideration that plasma NGF levels have been shown to be elevated in asthmatic patients, our result points to an important role for NGF in the pathogenesis of asthma.American Journal of Respiratory and Critical Care Medicine 06/1999; 159(5 Pt 1):1541-4. · 11.04 Impact Factor
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ABSTRACT: A number of topical aspects of histamine or methacholine inhalation tests were discussed. First, the reporting of results as the dose delivered to the mouth by the method of aerosol generation and inhalation may allow better interpretation of results between laboratories. However, this requires investigation. Second, the histamine or methacholine dose-response curve differs in asthmatics with a moderate to severe increase in airway responsiveness from asthmatics with a mild increase in responsiveness or nonasthmatics. In the latter groups, the dose-response curve is positioned to the right and has a maximal response plateau. The disappearance of this limited maximal airway narrowing in asthmatics appears to be due to added abnormalities. Third, histamine or methacholine inhalation tests provide a sensitive and specific measure of the presence of variable airflow obstruction (asthma). They are useful to validate the diagnosis when symptoms are suggestive but spirometry is normal. The symptoms of asthma are not specific, and without objective confirmation the diagnosis is frequently misjudged even by the specialist. Finally, airway hyperresponsiveness to histamine or methacholine is not diagnostic of asthma when chronic airflow limitation is present; hyperresponsiveness to isocapnic hyperventilation may be more specific.Respiration 02/1986; 50 Suppl 2:72-6. · 2.62 Impact Factor